Anti-ferroptotic PRKAA2 serves as a potential diagnostic and prognostic marker for hepatoblastoma.

Background: The incidence rate of hepatoblastoma (HB), which is the most prevalent malignant tumour among children, rises each year. According to recent studies, a number of neoplastic disorders and ferroptosis are intimately connected. This study aims to identify key ferroptosis-related genes in HB and explore new directions for the diagnosis and treatment of HB. Methods: Differentially expressed ferroptosis-related genes were identified using the Gene Expression Omnibus datasets. The functional annotation of candidate genes was evaluated through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. Machine learning and receiver operating characteristic (ROC) curves revealed protein kinase AMP-activated catalytic subunit alpha 2 (PRKAA2), tribbles homolog 2 (TRIB2), and liver-type glutaminase (GLS2) as potential diagnostic genes of HB. By using quantitative reverse transcription polymerase chain reaction (qRT-PCR) and immunohistochemistry, relative expression of PRKAA2 was examined. The effect of PRKAA2 on proliferation, apoptosis, and ferroptosis of HB cells was verified in vitro and in vivo. Fisher's exact test was used to evaluate the clinical significance of PRKAA2 in HB. Results: The prognostic indicators had a substantial correlation with PRKAA2 expression, which rose dramatically in HB tissues. PRKAA2 promotes proliferation and inhibits ferroptosis in HB cells. PRKAA2 plays a role in ferroptosis by regulating hypoxia-inducible factor 1α (HIF-1α) and transferrin receptor 1 (TFR1). Conclusions: PRKAA2 functions as a tumor-promoting factor in HB by promoting cell proliferation and prohibiting ferroptosis. Ferroptosis-related genes PRKAA2 is a potential diagnostic and prognostic marker for HB as well as a novel therapeutic target in the future.

Correction: Li et al. m6A mRNA Methylation Regulates LKB1 to Promote Autophagy of Hepatoblastoma Cells through Upregulated Phosphorylation of AMPK. Genes 2021, 12, 1747.

In the original publication [...].

Identification of key enzalutamide-resistance-related genes in castration-resistant prostate cancer and verification of RAD51 functions.

Patients with castration-resistant prostate cancer (CRPC) often develop drug resistance after treatment with enzalutamide. The goal of our study was to identify the key genes related to enzalutamide resistance in CRPC and to provide new gene targets for future research on improving the efficacy of enzalutamide. Differential expression genes (DEGs) associated with enzalutamide were obtained from the GSE151083 and GSE150807 datasets. We used R software, the DAVID database, protein-protein interaction networks, the Cytoscape program, and Gene Set Cancer Analysis for data analysis. The effect of RAD51 knockdown on prostate cancer (PCa) cell lines was demonstrated using Cell Counting Kit-8, clone formation, and transwell migration experiments. Six hub genes with prognostic values were screened (RAD51, BLM, DTL, RFC2, APOE, and EXO1), which were significantly associated with immune cell infiltration in PCa. High RAD51, BLM, EXO1, and RFC2 expression was associated with androgen receptor signaling pathway activation. Except for APOE, high expression of hub genes showed a significant negative correlation with the IC50 of Navitoclax and NPK76-II-72-1. RAD51 knockdown inhibited the proliferation and migration of PC3 and DU145 cell lines and promoted apoptosis. Additionally, 22Rv1 cell proliferation was more significantly inhibited with RAD51 knockdown than without RAD51 knockdown under enzalutamide treatment. Overall, six key genes associated with enzalutamide resistance were screened (RAD51, BLM, DTL, RFC2, APOE, and EXO1), which are potential therapeutic targets for enzalutamide-resistant PCa in the future.

O-GlcNAcylated LARP1 positively regulated by circCLNS1A facilitates hepatoblastoma progression through DKK4/ß-catenin signalling.

BACKGROUND: Accumulating studies have shown that La-related protein 1 (LARP1) is involved in the occurrence and development of various tumours. However, the expression pattern and biological role of LARP1 in hepatoblastoma (HB) remain unclear so far. METHODS: LARP1 expression level in HB and adjacent normal liver tissues was analysed by qRT-PCR, Western blotting and immunohistochemistry assays. The prognostic significance of LARP1 was evaluated by Kaplan-Meier method and multivariate Cox regression analysis. In vitro and in vivo functional assays were implemented to clarify the biological effects of LARP1 on HB cells. Mechanistically, the regulatory roles of O-GlcNAcylation and circCLNS1A in LARP1 expression were investigated by co-immunoprecipitation (co-IP), immunofluorescence, RNA immunoprecipitation (RIP), RNA pull-down and protein stability assays. Moreover, RNA-sequencing, co-IP, RIP, mRNA stability and poly(A)-tail length assays were performed to investigate the association between LARP1 and DKK4. The expression and diagnostic significance of plasma DKK4 protein in multi-centre cohorts were evaluated by ELISA and ROC curves. RESULTS: LARP1 mRNA and protein levels were remarkably elevated in HB tissues and associated with worse prognosis of HB patients. LARP1 knockdown abolished cell proliferation, triggered cell apoptosis in vitro as well as prohibited tumour growth in vivo, whereas LARP1 overexpression incited HB progression. Mechanistically, O-GlcNAcylation of LARP1 Ser672 by O-GlcNAc transferase strengthened its binding to circCLNS1A and then protected LARP1 from TRIM-25-mediated ubiquitination and proteolysis. LARP1 upregulation subsequently led to DKK4 mRNA stabilisation by competitively interacting with PABPC1 to prevent DKK4 mRNA from B-cell translocation gene 2-dependent deadenylation and degradation, thus facilitating ß-catenin protein expression and nuclear import. CONCLUSION: This study indicates that upregulated protein level of O-GlcNAcylated LARP1 mediated by circCLNS1A promotes the tumorigenesis and progression of HB through LARP1/DKK4/ß-catenin axis. Hence, LARP1 and DKK4 are promising therapeutical target and diagnostic/prognostic plasma biomarker for HB.

Characteristics of Prognostic Programmed Cell Death-Related Long Noncoding RNAs Associated With Immune Infiltration and Therapeutic Responses to Colon Cancer.

Programmed cell death (PCD) plays an important role in the onset and progression of various cancers. The molecular events surrounding the occurrence of abnormally expressed long noncoding RNAs (lncRNAs) leading to colon cancer (CC) have become a focus. We comprehensively evaluated the roles of PCD-related lncRNAs in the clinical management of CC and their immune responses. Therefore, we screened 41 prognostic PCD-related lncRNAs in The Cancer Genome Atlas database using co-expression analysis and assigned patients to groups according to the results of cluster analysis. The immune response and functions of cluster 2 were substantially suppressed, which might explain the poor prognosis in this group. A prognostic model comprising eight PCD-related lncRNAs was developed, and its effectiveness was verified using an external database. High-and low-risk groups had different epigenetic modifications and changes in immune cell infiltration. Patients in the high-risk group were resistant to immunotherapy and various chemotherapeutic drugs. Studies in vitro and in vivo further confirmed a carcinogenic role of the lncRNA U62317.4. Our findings of the prognostic value of PCD-related lncRNAs revealed their important roles in immune response disorders, thus providing valuable insights into the clinical management and molecular mechanisms of CC.

The N6-methyladenosine modification enhances ferroptosis resistance through inhibiting SLC7A11 mRNA deadenylation in hepatoblastoma.

BACKGROUND: Solute carrier family 7 member 11 (SLC7A11) is overexpressed in multiple human tumours and functions as a transporter importing cystine for glutathione biosynthesis. It promotes tumour development in part by suppressing ferroptosis, a newly identified form of cell death that plays a pivotal role in the suppression of tumorigenesis. However, the role and underlying mechanisms of SLC7A11-mediated ferroptosis in hepatoblastoma (HB) remain largely unknown. METHODS: Reverse transcription quantitative real-time PCR (RT-qPCR) and western blotting were used to measure SLC7A11 levels. Cell proliferation, colony formation, lipid reactive oxygen species (ROS), MDA concentration, 4-HNE, GSH/GSSG ratio and cell death assays as well as subcutaneous xenograft experiments were used to elucidate the effects of SLC7A11 in HB cell proliferation and ferroptosis. Furthermore, MeRIP-qPCR, dual luciferase reporter, RNA pulldown, RNA immunoprecipitation (RIP) and RACE-PAT assays were performed to elucidate the underlying mechanism through which SLC7A11 was regulated by the m6A modification in HB. RESULTS: SLC7A11 expression was highly upregulated in HB. SLC7A11 upregulation promoted HB cell proliferation in vitro and in vivo, inhibiting HB cell ferroptosis. Mechanistically, SLC7A11 mRNA exhibited abnormal METTL3-mediated m6A modification, which enhanced its stability and expression. IGF2 mRNA-binding protein 1 (IGF2BP1) was identified as the m6A reader of SLC7A11, enhancing SLC7A11 mRNA stability and expression by inhibiting SLC7A11 mRNA deadenylation in an m6A-dependent manner. Moreover, IGF2BP1 was found to block BTG2/CCR4-NOT complex recruitment via competitively binding to PABPC1, thereby suppressing SLC7A11 mRNA deadenylation. CONCLUSIONS: Our findings demonstrated that the METTL3-mediated SLC7A11 m6A modification enhances HB ferroptosis resistance. The METTL3/IGF2BP1/m6A modification promotes SLC7A11 mRNA stability and upregulates its expression by inhibiting the deadenylation process. Our study highlights a critical role of the m6A modification in SLC7A11-mediated ferroptosis, providing a potential strategy for HB therapy through blockade of the m6A-SLC7A11 axis.

m6A mRNA Methylation Regulates LKB1 to Promote Autophagy of Hepatoblastoma Cells through Upregulated Phosphorylation of AMPK.

The N6-methyladenosine (m6A) RNA modification can regulate autophagy to modulate the growth and development of tumors, but the mechanism of m6A modification for the regulation of autophagy in hepatocellular carcinoma cells (HCC) remains unclear. In the study, the knockdown of the Wilms' tumor 1-associating protein (WTAP) was made in HCC to study the correlation between m6A modification and autophagy. A fluorescent confocal microscopy analysis showed that the knockdown of WTAP could facilitate the autophagy of HCC. A Western blot analysis showed that the level of p-AMPK was decreased in WTAP-knockdown HCC cells. Additionally, LKB1, the upstream kinase of AMPK, was regulated by WTAP and it could mediate the phosphorylation of AMPK in an m6A-dependent manner. Further studies revealed that the knockdown of WTAP could reduce the level of LKB1 mRNA with m6A. This could result in the increased stability of LKB1 mRNA to promote its expression. The knockdown of WTAP could upregulate the level of autophagy and inhibit HCC proliferation. However, the overexpression of WTAP could resist autophagic cell death.

Comprehensive Analysis of Glycolysis-Related Genes for Prognosis, Immune Features, and Candidate Drug Development in Colon Cancer.

The dysregulated expression of glycolysis-related genes (GRGs) is closely related to the occurrence of diverse tumors and regarded as a novel target of tumor therapy. However, the role of GRGs in colon cancer is unclear. We obtained 226 differential GRGs (DE-GRGs) from The Cancer Genome Atlas (TCGA) database. Cox regression analysis was used to construct a DE-GRG prognostic model, including P4HA1, PMM2, PGM2, PPARGC1A, PPP2CB, STC2, ENO3, and CHPF2. The model could accurately predict the overall survival rate of TCGA and GSE17536 patient cohorts. The risk score of the model was closely related to a variety of clinical traits and was an independent risk factor for prognosis. Enrichment analysis revealed the activation of a variety of glycolysis metabolism and immune-related signaling pathways in the high-risk group. High-risk patients displayed low expression of CD4+ memory resting T cells and resting dendritic cells and high expression of macrophages M0 compared with the expression levels in the low-risk patients. Furthermore, patients in the high-risk group had a higher tumor mutation load and tumor stem cell index and were less sensitive to a variety of chemotherapeutic drugs. Quantitative reverse transcription polymerase chain reaction and immunohistochemistry analyses validated the expression of eight GRGs in 43 paired clinical samples. This is the first multi-omics study on the GRGs of colon cancer. The establishment of the risk model may benefit the prognosis and drug treatment of patients.

Identification and Exploration of Novel Macrophage M2-Related Biomarkers and Potential Therapeutic Agents in Endometriosis.

Endometriosis (EM) is a chronic neuroinflammatory disorder that is associated with pain and infertility that affects ∼10% of reproductive-age women. The pathophysiology and etiology of EM remain poorly understood, and diagnostic delays are common. Exploration of the underlying molecular mechanism, as well as novel diagnostic biomarkers and therapeutic targets, is urgently needed. Inflammation is known to play a key role in the development of lesions, which are a defining feature of the disorder. In our research, the CIBERSORT and WGCNA algorithms were used to establish a weighted gene co-expression network and to identify macrophage-related hub genes using data downloaded from the GEO database (GSE11691, 7305). The analysis identified 1,157 differentially expressed genes (DEGs) in EM lesions, of which five were identified as being related to M2 macrophages and were validated as differentially expressed by qRT-PCR and immunohistochemistry (IHC). Of these putative novel biomarker genes, bridging integrator 2 (BIN2), chemokine receptor 5 (CCR5), and macrophage mannose receptor 1 (MRC1) were upregulated, while spleen tyrosine kinase (SYK) and metalloproteinase 12 (ADAM12) were downregulated in ectopic endometria vs. normal endometria. Meanwhile, 23 potentially therapeutic small molecules for EM were obtained from the cMAP database, among which topiramate, isoflupredone, adiphenine, dexverapamil, MS-275, and celastrol were the top six molecules with the highest absolute enrichment values. This is our first attempt to use the CIBERSORT and WGCNA algorithms for the identification of novel Mϕ2 macrophage-related biomarkers of EM. Our findings provide novel insights into the impact of immune cells on the etiology of EM; nevertheless, further investigation of these key genes and therapeutic drugs is needed to validate their effects on EM.

Dynamic analysis of m6A methylation spectroscopy during progression and reversal of hepatic fibrosis.

Aim: To dynamically analyze the differential m6A methylation during the progression and reversal of hepatic fibrosis. Materials & methods: We induced hepatic fibrosis in C57/BL6 mice by intraperitoneal injection of CCl4. The reversal model of hepatic fibrosis was established by stopping drug after continuous injection of CCl4. Dynamic m6A methylation was evaluated using MeRIP-Seq in the progression and reversal of hepatic fibrosis at different stages. Result: During the hepatic fibrosis, differential m6A methylation was mainly enriched in processes associated with oxidative stress and cytochrome metabolism, while differential m6A methylation was mainly enriched in processes associated with immune response and apoptosis in the hepatic fibrosis reversal. Conclusion: m6A methylation plays an important role in the progression and reversal of hepatic fibrosis.

A predictive analysis approach for paediatric and adult high-grade glioma: miRNAs and network insight.

BACKGROUND: Brain tumours are the most common solid tumour in children and are a cause of mortality in adults. Most cases of brain tumour-related death are attributed to glioblastoma (GBM), with an elevated rate for high-grade glioma (HGG). Showing strong heterogeneity, the lesion location, molecule expression and type of HGG differ between adults and children. However, with regard to pathogenesis, brain tumours are expected to have the same underlying molecular processes. METHODS: In this study, we obtained data from the Gene Expression Omnibus (GEO) database to analyse molecular expression in HGG between adults and children. The same and different mutations were identified in these groups, and the genes involved were compared using Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Molecular analysis revealed the same trend of differences between children and adults, which was verified in The Cancer Genome Atlas (TCGA). RESULTS: A total of 12 microarrays including 455 HGG patients were screened. Through a rigorous intersecting process, we identified miR-10a, miR-10b, and miR-139 as having common differences, as well as 6 target genes, such as CDK6, SOX4 and VEGFA, etc. And 12 long noncoding RNAs (lncRNAs). CONCLUSIONS: We identified that these key molecules are involved in development and progression of HGG between adults and children. The findings provide a comprehensive description of the similarities in advanced diseases between adults and children and molecular diagnostic directions for precision small-molecule medicine to treat HGG in different age populations.

Knockdown of NRAGE Impairs Homologous Recombination Repair and Sensitizes Hepatoblastoma Cells to Ionizing Radiation.

Background: NRAGE (neurotrophin receptor-interacting melanoma antigen-encoding gene homolog) has a complex role and regulates cell growth in different tumor cells. Although NRAGE was been discovered for more than 10 years ago, the function of NRAGE in hepatoblastoma (HB) cells is currently unknown. Materials and Methods: The expression of NRAGE was detected by reverse transcription-quantitative polymerase chain reaction assay or western blotting assay. Cellular apoptosis was analyzed to estimate the effect of NRAGE under radiation. The ability of clonogenic capacity was evaluated to confirm the influence of proliferation for NRAGE by radiation. The immunofluorescence assay was used to further study the expression of NRAGE under radiation. A nude mouse tumor xenograft model was constructed to confirm the effect of NRAGE deficiency under radiation conditions in vivo. Results: The authors determined that deletion of NRAGE significantly inhibited HB cell proliferation in vitro and in vivo, and NRAGE knockdown apparently sensitized HB cells to ionizing radiation (IR). Further mechanistic studies revealed that NRAGE plays a critical role in homologous recombination by inhibiting the expression of RNF8 (ring finger protein 8) and BARD1 (BRCA1 associated RING domain 1) and the recruitment of RAD51. Conclusions: The authors demonstrated that downregulation of NRAGE sensitizes HB cell lines to IR in vitro and in vivo. It provides a promising therapeutic strategy for HB patients by specifically targeting NRAGE.

Serum miR-515-3p, a potential new RNA biomarker, is involved in gastric carcinoma.

OBJECTIVES: microRNAs (miRNAs) have provided a new opportunity for developing diagnostic biomarkers and effective therapeutic targets in gastric cancer (GC). In this study, we aimed to investigate the relationship between miR-515-3p and GC development. EXPERIMENTAL DESIGN: The Gene Expression Omnibus (GEO) database was used for screening genes and miRNA and for 2R analysis. miRNA prediction target genes and screening key genes were analyzed using protein interactions (PPI) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. A network of miRNA-mRNA interactions was predicated by Cytoscape (v.3.5.1), Institute of Systems Biology & University of California, San Diego & Pasteur institute & University of California, San Francisco. Finally, miR-515-3p levels were detected by quantitative reverse-transcription polymerase chain reaction (qRT-PCR) in gastric cells and plasma levels. Then, the association between the expression level of miR-515-3p and the clinicopathological features of patients with GC was further analyzed. OBSERVATIONS AND CONCLUSIONS: We found that miR-515-3p was markedly overexpressed in individuals with GC compared with that in normal gastric cells (NCs) and the surgery group (P < 0.0001). In addition, receiver operating characteristic (ROC) analysis yielded an area under the curve (AUC) value of 0.8555 for miR-515-3p. SIGNIFICANCE: Our results present new information to the field of gastric cancer and has done a good job of creating an initial hypothesis using the database as well as validate their initial results. These results suggest that serum miR-515-3p is a novel potential biomarker for the detection of GC.

CircHMGCS1 Promotes Hepatoblastoma Cell Proliferation by Regulating the IGF Signaling Pathway and Glutaminolysis.

Circular RNAs (circRNAs), a novel class of endogenous RNAs, have been recently shown to participate in cellular development and several pathophysiological processes. The identification of dysregulated circRNAs and their function in cancer have attracted considerable attention. Nevertheless, the expression profile and role of circRNAs in human hepatoblastoma (HB) remain to be studied. In this report, we analyzed the expression prolife of circRNAs in HB tissues and identified circHMGCS1 (3-hydroxy-3-methylglutaryl-CoA synthase 1; hsa_circ_0072391) as a remarkably upregulated circRNA. Methods: The expression prolife of circRNAs in HB tissues were investigated through circRNA sequencing analyses. ISH and qRT-PCR assays were performed to measure the expression level of circHMGCS1. The effect of knocking down circHMGCS1 in HB cells in vitro and in vivo were evaluated by colony formation assay, flow cytometry, xenograft tumors assay and untargeted metabolomics assay. MRE analysis and dual luciferase assay were performed to explore the underlying molecular mechanisms. Results: HB patients with high circHMGCS1 expression have shorted overall survival. Knockdown of circHMGCS1 inhibits HB cells proliferation and induces apoptosis. CircHMGCS1 regulates IGF2 and IGF1R expression via sponging miR-503-5p, and affects the downstream PI3K-Akt signaling pathway to regulate HB cell proliferation and glutaminolysis. Conclusions: The circHMGCS1/miR-503-5p/IGF-PI3K-Akt axis regulates the proliferation, apoptosis and glutaminolysis of HB cells, implying that circHMGCS1 is a promising therapeutic target and prognostic marker for HB patients.

(-)-Guaiol regulates autophagic cell death depending on mTOR signaling in NSCLC.

(-)-Guaiol, a sesquiterpene alcohol with the guaiane skeleton, has been found in many Chinese medicinal plants and been reported to comprise various guaiane natural products that are well known for their antibacterial activities. Previously, we have shown its antitumor activity by inducing autophagy in NSCLC cells. However, its potential mechanism in inducing autophagy is still under our investigation. Here, data from our western blotting assays showed that, in NSCLC cells, (-)-Guaiol significantly blocked the mTORC2-AKT signaling by suppressing mTOR phosphorylation at serine 2481 (S2481) to induce autophagy, illustrated by the increasing ratio of LC3II/I. Besides, it impaired the mTORC1 signaling by inhibiting the activity of its downstream factors, such as 4E-BP1 and p70 S6K, all of which could obviously rescued by the mTOR activator MHY1485. Afterwards, results from biofunctional assays, including cell survival analysis, colony formation assays and flow cytometry assays, suggested that (-)-Guaiol triggered autophagic cell death by targeting both mTORC1 and mTORC2 signaling pathways. In summary, our studies showed that (-)-Guaiol inhibited the proliferation of NSCLC cells by specifically targeting mTOR signaling pathways, including both mTORC1 and mTORC2 signaling, providing a better therapeutic option for substituting rapamycin in treating NSCLC patients.

Combining multi-dimensional data to identify a key signature (gene and miRNA) of cisplatin-resistant gastric cancer.

Gastric cancer (GC) is one of the most lethal malignant tumors; the resistance of this type of tumor is the main source of GC treatment failure. In this study, we used bioinformatics analysis to verify differences in resistant GCs and identify an effective method for reversing drug resistance in GC. Microarray data [gene and microRNA (miRNA)] were analyzed using GEO2R software, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were applied to further enrich the genetic data. miRNA-gene interactions were determined using Cytoscape (v.3.5.1). Online software was used to analyze protein interactions and predict network structure. The Cancer Genome Atlas (TCGA) database was used to verify the expression levels of genes in GC resistance. miR-604 expression levels were verified by real-time PCR in GC cell lines. We screened 3981 GC resistance-associated genes and 244 miRNAs using bioinformatics methods. Six hub genes were identified and verified in the TCGA database, including five up-regulated genes, POLR2L, POLR2C, POLR2F, APRT, and LMAN2, and a down-regulated gene, NFKB2. The up-regulated genes POLR2L, POLR2C, APRT, and LMAN2 interact with miR-604; therefore, we focused on miR-604, which has low expression in drug-resistant GC. The results of this study indicate that through bioinformatics technologies, we have determined the hub genes and hub miRNAs related to drug resistance in GC. Among them, miR-604 could become a new indicator in the diagnosis of drug-resistant GC and may be used to investigate the pathogenesis of resistance in GC.

Apoptin-derived peptide reverses cisplatin resistance in gastric cancer through the PI3K-AKT signaling pathway.

The prognosis of gastric cancer (GC) remains poor due to clinical drug resistance, and novel drugs are urgently needed. Apoptin-derived peptide (AdP) is an antitumor polypeptide constructed in our laboratory that has been used to combat cisplatin (CDDP) resistance in GC cells. MTT and colony-formation assays and Hoechst 33342 staining were used to measure the cytotoxicity of CDDP and AdP in GC cells. Cell apoptosis was measured using an Annexin-V-FITC/PI dual staining assay. Western blot analysis was conducted to detect the expression of proteins in the PI3K/AKT signaling pathway and resistance-related markers. AdP exerted a specific cytotoxic effect on GC cells and CDDP-resistant GC cells in a concentration- and time-dependent manner. AdP also suppressed cell invasion and migration. Additionally, AdP inhibited the expression of p85, AKT, p-p85, p-AKT, multidrug resistance 1 (MDR1), and aryl hydrocarbon nuclear translocator (ARNT) in the PI3K/AKT/ARNT signaling pathway, which promoted apoptosis and necrosis in GC cells. AdP promoted apoptosis in CDDP-resistant GC cells by suppressing the PI3K/AKT/ARNT signaling pathway and might be considered a candidate agent for the clinical treatment of cisplatin-resistant GC.

Metastatic leiomyosarcoma presenting as a lung mass with left atrial extension: case report and anesthetic management.

INTRODUCTION: Lung metastasis of leiomyosarcoma that protrudes into the left atrium is an extremely rare condition. Severe complications may occur that prominently increase the mortality during the perioperative period. Currently, the anesthetic management reports are limited and there is no generally acknowledged algorithm available. CASE PRESENTATION: A 67-year-old man presented with cough and dyspnea for 10 days. Workup revealed bilateral pulmonary effusion. Transthoracic echocardiography showed a large mass in the left atrium. Urgent surgical resection under cardiopulmonary bypass was performed. We focused on oxygenation improvement and cardiac function management by applying protective ventilation with low positive end expiratory pressure, low dose inotropic agents, and other methods to maintain stable homeostasis. Results of biopsy established a diagnosis of metastatic leiomyosarcoma. CONCLUSION: We reported a case of metastatic leiomyosarcoma presenting as a lung mass with left atrial extension and anesthetic management during surgical resection. Treating acute heart failure and refractory hypoxemia was the key focus perioperatively.

RAP80 is an independent prognosis biomarker for the outcome of patients with esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is the most popular pathology of esophageal cancer (EC) in China, especially in Henan province, mid-east of China. Presently, targeting DNA damage repair (DDR) factors is a promising approach for cancer therapy. Our group has been focusing on exploring the DDR factors overexpressed in ESCC tissues to provide potential targets for therapies for many years. RAP80/UIMC1 (ubiquitin interaction motif containing 1), one of those DDR factors we tested, was highly overexpressed in ESCC tissues compared with adjacent normal tissues. Moreover, the RAP80 mRNA level was validated to be an independent prognosis biomarker for the overall survival time of ESCC patients. The following biological assays revealed that it promoted cell proliferation both in vitro and in vivo, inhibited cell apoptosis at both early and late stages, and participated in G2/M checkpoint regulation. Even though studies have reported that ATM phosphorylates RAP80 at different serine sites upon DNA damage, the reversal regulation of RAP80 on the activity of ATM has never been investigated. In the study, mechanism explorations revealed that RAP80 positively regulated the ATM activity via proteasome-ubiquitination pathway to promote the transition of G2/M phase in cell cycle. By examining a number of E3 ubiquitination ligases (Ub) and deubiquitination (DUb) enzymes, we found that RAP80 positively regulated the stability of USP13 to promote cell proliferation of EC cells. Moreover, inhibition of RAP80 greatly sensitized EC cells to ATM inhibitor KU-55933, triggering a potential combination of RAP80 inhibitors and ATM inhibitors to enhance the therapeutic efficiency of ESCC patients for the clinicians.

Sirtuin 6 plays an oncogenic role and induces cell autophagy in esophageal cancer cells.

Sirtuin 6, a member of sirtuin family, is generally regarded as a tumor suppressor as it participates in suppressing hypoxia-inducible factor 1α and MYC transcription activity by deacetylating H3K9 (histone H3 lysine 9) and H3K56 (histone H3 lysine) at promoters of target genes, leading to the aerobic glycolysis inhibition and cell growth suppression. However, its expression has recently been reported to be highly elevated in a series of tumors, including prostate cancer, breast cancer, and non-small cell lung cancer, indicating that sirtuin 6 plays dual roles in tumorigenicity in a cell/tumor type-specific manner. To our knowledge, the biological roles of sirtuin 6 in esophageal cancer cells have still been underestimated. In the study, data from quantitative reverse transcriptase polymerase chain reaction-based assays and immunohistochemical assays revealed that sirtuin 6 was remarkably overexpressed in esophageal squamous tumor tissues. Moreover, its upregulation was closely related with clinical features, such as gender, pathology, tumor-node-metastasis, and cell differentiation. Subsequently, the biological tests showed that it promoted cell proliferation and induced the expression of Bcl2, a key anti-apoptotic factor, in esophageal carcinoma cells. Moreover, using the ratio of LC3II/I, a widely recognized autophagy biomarker, we showed that it apparently induced cell autophagy, which was further confirmed by the autophagy flux assays. In addition, results from western blotting assays and immunoprecipitation assays displayed that sirtuin 6 specifically interacted with ULK1 and positively regulated its activity by inhibiting its upstream factor mammalian target of rapamycin activity. In summary, our studies shed insights into the crucial functions of sirtuin 6 in esophageal carcinoma cells and provide evidence supporting sirtuin 6-based personalized therapies in esophageal carcinoma cell patients.